Glucose-based Dialysis Solutions Research Articles

Aging of the Peritoneal Dialysis Membrane.

Long-term peritoneal dialysis as currently performed, causes structural and functional alterations of the peritoneal dialysis membrane. This decay is brought about by the continuous exposure to commercially available glucose-based dialysis solutions. This review summarizes our knowledge on the peritoneum in the initial phase of PD, during the first 2 years and the alterations in function and morphology in long-term PD patients. The pseudohypoxia hypothesis is discussed and how this glucose-induced condition can be used to explain all peritoneal alterations in long-term PD patients. Special attention is paid to the upregulation of hypoxia inducing factor-1 and the subsequent stimulation of the genes coding for glucose transporter-1 (GLUT-1) and the growth factors transforming growth factor-β (TGFβ), vascular endothelial growth factor (VEGF), plasminogen growth factor activator inhibitor-1 (PAI-1) and connective tissue growth factor (CTGF). It is argued that increased pseudohypoxia-induced expression of GLUT-1 in interstitial fibroblasts is the key factor in a vicious circle that augments ultrafiltration failure. The practical use of the protein transcripts of the upregulated growth factors in peritoneal dialysis effluent is considered. The available and developing options for prevention and treatment are examined. It is concluded that low glucose degradation products/neutral pH, bicarbonate buffered solutions with a combination of various osmotic agents all in low concentration, are currently the best achievable options, while other accompanying measures like the use of RAAS inhibitors and tamoxifen may be valuable. Emerging developments include the addition of alanyl glutamine to the dialysis solution and perhaps the use of nicotinamide mononucleotide, available as nutritional supplement.

Exposition to glucose-based peritoneal dialysis fluids exacerbates adipocyte lipolysis and glycogen storage in rat adipose cells.

Glucose absorption during peritoneal dialysis (PD) is suspected to promote visceral fat accretion and weight gain in PD patients. The current study was designed to test the impact of glucose-based PD fluids on adipose cell lipolysis and glycogen content. Rat adipose cells, isolated from epididymal fat pad, were exposed to a 30 vol./70 vol. mixture of glucose-based dialysis solutions (containing 1.36% and 3.86% glucose, Physioneal 35®; Baxter) or Krebs-Henseleit buffer for 4 h. Adipose cells were further incubated with laboratory-made solutions containing 1.36% and 3.86% glucose or mannitol as an osmotic control. Baseline and noradrenaline-stimulated lipolysis was measured, and glycogen content assayed. The glucose-based commercial PD fluids as well as the laboratory-manufactured high glucose solutions exacerbated lipolysis in baseline and noradrenaline conditions and increased glycogen stores in adipose cells. Mannitol solutions (1.36% and 3.86%) used as an osmotic control did not produce such effects. This study provides the first evidence that glucose-based dialysis solutions increase basal as well as stimulated lipolysis in adipocytes, an effect that is directly attributable to high concentrations of glucose per se.

Identification of Gene Transcripts Implicated in Peritoneal Membrane Alterations.

♦ BACKGROUND: Permanent stimulation of the peritoneum during peritoneal dialysis (PD) is likely to result in increased expression of genes encoding proteins involved in inflammation and tissue remodeling. Peritoneal fibrosis and neoangiogenesis may develop. ♦ OBJECTIVE: To assess highly expressed genes potentially in volved in peritoneal alterations during PD treatment using an animal model. ♦ METHODS: A PD catheter was implanted in 36 male Wistar rats after 70% nephrectomy. The rats were divided into 3 groups, exposed to dialysis solution for 8 weeks, and sacrificed 2 weeks later. Group B was exposed to a buffer, group D was exposed to a 3.86% glucose-based dialysis solution, and in group D+H, a second hit of intraperitoneal blood on top of the dialysis solution was given to induce the development of peritoneal sclerosis. Before sacrifice, peritoneal function was assessed. Omental tissue was obtained for analysis of gene expression using RT-qPCR. ♦ RESULTS: Fibrosis scores, vessel counts, and peritoneal function parameters were not different between the groups. Genes involved in the transforming growth factor beta signaling pathway, cell proliferation, angiogenesis, and inflammation were more expressed (p < 0.05) in the D+H group. Almost no differences were found between the control groups. We identified 4 genes that were related to peritoneal transport. ♦ CONCLUSION: Already a mid-term peritoneal exposure, when no microscopical and functional alterations are present, provokes activation of gene pathways of cell proliferation, fibrosis, neoangiogenesis, and inflammation.

New Insights into the Effects of Chronic Kidney Failure and Dialysate Exposure on the Peritoneum.

♦ INTRODUCTION: Chronic uremia and the exposure to dialysis solutions during peritoneal dialysis (PD) induce peritoneal alterations. Using a long-term peritoneal exposure model, we compared the effects of chronic kidney failure (CKD) itself and exposure to either a 'conventional' or a 'biocompatible' dialysis solution on peritoneal morphology and function. ♦ METHODS: Wistar rats (Harlan, Zeist, the Netherlands) were grouped into: normal kidney function (NKF), CKD induced by 70% nephrectomy, CKD receiving daily peritoneal infusions with 3.86% glucose Dianeal (CKDD), or Physioneal (both solutions from Baxter Healthcare, Castlebar, Ireland) (CKDP). At 16 weeks, a peritoneal function test was performed, and histology, ultrastructure, and hydroxyproline content of peritoneal tissue were assessed. ♦ RESULTS: Comparing CKD with NKF, peritoneal transport rates were higher, mesothelial cells (MC) displayed increased number of microvilli, blood and lymph vasculature expanded, vascular basal lamina appeared thicker, with limited areas of duplication, and fibrosis had developed. All alterations, except lymphangiogenesis, were enhanced by exposure to both dialysis fluids. Distinct MC alterations were observed in CKDD and CKDP, the latter displaying prominent basolateral protrusions. In addition, CKDP was associated with a trend towards less fibrosis compared to CKDD. ♦ CONCLUSIONS: Chronic kidney failure itself induced peritoneal alterations, which were in part augmented by exposure to glucose-based dialysis solutions. Overall, the conventional and biocompatible solutions had similar long-term effects on the peritoneum. Importantly, the latter may attenuate the development of fibrosis.

The Natural Time Course of Membrane Alterations During Peritoneal Dialysis Is Partly Altered by Peritonitis.

♦ The quality of the peritoneal membrane can deteriorate over time. Exposure to glucose-based dialysis solutions is the most likely culprit. Because peritonitis is a common complication of peritoneal dialysis (PD), distinguishing between the effect of glucose exposure and a possible additive effect of peritonitis is difficult. The aim of the present study was to compare the time-course of peritoneal transport characteristics in patients without a single episode of peritonitis-representing the natural course-and in patients who experienced 1 or more episodes of peritonitis during long-term follow-up. ♦ This prospective, single-center cohort study enrolled incident adult PD patients who started PD during 1990-2010. A standard peritoneal permeability analysis was performed in the first year of PD treatment and was repeated every year. The results in patients without a single episode of peritonitis ("no-peritonitis group") were compared with the results obtained in patients who experienced 1 or more peritonitis episodes ("peritonitis group") during a follow-up of 4 years. ♦ The 124 patients analyzed included 54 in the no-peritonitis group and 70 in the peritonitis group. The time-course of small-solute transport was different in the groups, with the peritonitis group showing an earlier and more pronounced increase in the mass transfer area coefficient for creatinine (p = 0.07) and in glucose absorption (p = 0.048). In the no-peritonitis group, the net ultrafiltration rate (NUFR) and the transcapillary ultrafiltration rate (TCUFR) both showed a steep increase from the 1st to the 2nd year of PD that was absent in the peritonitis group. Both groups showed a decrease in the NUFR after year 3. A decrease in the TCUFR occurred only in the peritonitis group. That decrease was already present after the year 1 in patients with severe peritonitis. The time-course of free water transport showed a continuous increase in the patients without peritonitis, but a decrease in the patients who experienced peritonitis (p < 0.01). No difference was observed in the time-course of the effective lymphatic absorption rate. The time-courses of immunoglobulin G and α2-macroglobulin clearances showed a decrease in both patient groups, with a concomitant increase of the restriction coefficient. Those changes were not evidently influenced by peritonitis. The two groups showed a similar decrease in the mesothelial cell mass marker cancer antigen 125 during follow-up. ♦ On top of the natural course of peritoneal function, peritonitis episodes to some extent influence the time-course of small-solute and fluid transport-especially the transport of solute-free water. Those modifications increase the risk for overhydration.

Peri̇ton Di̇yali̇z Sıvıları (Peritoneal Dialysis Solutions)

Peritoneal dialysis (PD) is an important kidney replacement therapy for end stage renal disease (ESRD) patients. Patients easily adapt at home based treatment of PD. Standard traditional solutions uses glucose as an osmotic agent. Glucose based dialysis solutions contains high concentrations of glucose. They cause production of glucose degradation products and lactate. They have high osmolality, and low pH. All these features damage to the peritoneum by fibrosis and neoangiogenesis. Newer PD solutions were produced with alternative buffers and osmotic agents (icodextrin or amino acids). They have a higher pH and causes production of fewer glucose degradation products. With the usage of newer PD solutions we can achieve better metabolic controls of patients and body compositions. Peritoneal membrane viability increases by their less fibrotic and less inflammatory features of new solutions. But their effect on patient survival is not clearly identified yet. The aim of this review is to describe and to overview the different types of peritoneal dialysissolutions used during PD.

Randomized controlled study of icodextrin on the treatment of peritoneal dialysis patients during acute peritonitis

The clinical benefits of using icodextrin during acute peritonitis in peritoneal dialysis are uncertain. On the premise that high glucose concentration might jeopardize the peritoneal defense during peritonitis, icodextrin administration during acute peritonitis could have the potential to improve the peritonitis outcome whilst improving ultrafiltration. We conducted a single-center, open-label, randomized controlled trial in which 53 adult continuous ambulatory peritoneal dialysis patients underwent randomization to receive either icodextrin or original glucose-based dialysis solution. The primary outcome measure was the peritoneal dialyzate white cell count on Day 3. Secondary outcome measures comprised the need of additional hypertonic exchanges, fluid control as denoted by changes in body weight, and the clinical outcome of peritonitis including 30-day and 120-day all-cause mortality. Between icodextrin and control treatment groups, there were no statistically significant differences in the peritoneal dialyzate white cell count on day (1829 versus 987/mm(3), P = 0.13). There was neither improvement in primary cure rate (31.8 versus 32.3%, P = 1.00), nor was there any change in 120-day mortality after icodextrin use (13.6 versus 12.9%, P = 1.00). However, requirement of hypertonic dialysis exchange was much more frequent in the control group than in those randomized to icodextrin (35.5 versus 0%, P = 0.001). Body weight did not change significantly in the icodextrin group, but body weight in the control group increased from 63.3 ± 14.5 kg at baseline to 64.2 ± 14.2 kg at Day 5 (P = 0.0002) and 65.2 ± 14.1 kg at Day 10 (P < 0.0001). As compared with glucose-based peritoneal dialysis solution, use of icodextrin achieved better ultrafiltration and fluid control during acute peritonitis complicating continuous ambulatory peritoneal dialysis, although we found no evidence of a worthwhile clinical benefit on peritonitis resolution. (ClinicalTrial.gov number, NCT0104446 [ClinicalTrial.gov].).

An update on peritoneal dialysis solutions

Peritoneal dialysis (PD) has achieved its current position as the most commonly used home-based dialysis therapy--and with patient survival equal to that seen with hemodialysis--despite the use of glucose-based dialysis solutions with high concentrations of glucose, glucose degradation products and lactate, high osmolality, and low pH, features that are harmful both for the peritoneum and the patient. Newer PD solutions with alternative buffers, a higher pH and fewer glucose degradation products, or ones that contain icodextrin or amino acids as osmotic agents, have been introduced in many countries and have been shown to improve peritoneal membrane health and viability. Icodextrin solution enhances fluid and sodium removal, and the once-daily use of icodextrin and/or amino acid solutions can lessen the harmful effects caused by the exposure of the peritoneal membrane to glucose. However, whether the newer PD solutions improve patient survival over the older solutions is not clear. Use of PD therapy, with or without the newer PD solutions, is associated with an improvement in patient survival that is equivalent to that obtained with hemodialysis. Therefore, the conventional glucose-based solutions--despite their known negative features--continue to have a well-established role in PD therapy, particularly in the many countries where the newer PD solutions are not easily available.

Comparative analysis of lipid and glucose metabolism biomarkers in non-diabetic hemodialysis and peritoneal dialysis patients

To investigate and compare glucose and lipid metabolism biomarkers in non-diabetic peritoneal dialysis and hemodialysis patients. The study followed a prospective and cross-sectional design. Participants included all prevalent end-stage renal disease patients under renal replacement therapy treated in a university-based clinic. There were no interventions. Blood samples were taken after 8 hours of fasting. Insulin serum levels were determined by chemiluminescence. Insulin resistance were assessed by the insulin sensitivity check index (QUICKI) determined as follow: 1/[log(Io) + log(Go)], where Io is the fasting insulin, and Go is the fasting glucose. HOMA index was also measured: (FPG × FPI)/22.5; FPG = fasting plasma glucose (mmol/L); FPI = fasting plasma insulin (mU/mL). The others biochemical exams were measured utilizing the routine tests. We screened 154 patients (80 on hemodialysis and 74 on peritoneal dialysis). Seventy-four diabetic patients were excluded. Of the remaining 80 patients (55% males, mean age 52 ± 15 years), 35 were on peritoneal dialysis and 45 on hemodialysis. Fasting glucose of peritoneal dialysis patients compared to hemodialysis patients were 5.0 ± 0.14 versus 4,58 ± 0.14 mmol/L, p<0.05; glycated hemoglobin 5.9 ± 0.1 versus 5.5 ± 0.1%, p < 0.05; total cholesterol 5.06 ± 0.19 versus 3.39 ± 0.20 mmol/L, p < 0.01; LDL-c 2.93 ± 0.17 versus 1.60 ± 0.17 mmol/L, p < 0.01; and index HOMA 3.27 versus 1,68, p < 0,05. Importantly, all variables were adjusted for age, gender, dialysis vintage, calcium-phosphorus product, albumin and C-reactive protein levels. We observed a worst profile of lipid and glucose metabolism biomarkers in peritoneal dialysis patients (lower insulin sensitivity and higher fasting glucose, HbA1c, total cholesterol and LDL-c) when compared to hemodialysis, potentially due to the glucose-based dialysis solutions utilized in the peritoneal dialysis population.

Induction of Chronic Kidney Failure in a Long-Term Peritoneal Exposure Model in the Rat: Effects on Functional and Structural Peritoneal Alterations

A long-term peritoneal exposure model has been developed in Wistar rats. Chronic daily exposure to 3.86% glucose based, lactate buffered, conventional dialysis solutions is possible for up to 20 weeks and induces morphological abnormalities similar to those in long-term peritoneal dialysis (PD) patients. The possible effects of kidney failure in this model are unknown. The aim was to analyze the effects of chronic kidney failure on peritoneal function and morphology, alone and in combination with PD exposure, in a well-established, long term, peritoneal exposure model in the rat. ♢ 40 male Wistar rats were randomly assigned into four experimental groups: no nephrectomy, no peritoneal exposure (sham; n = 8); nephrectomy, no peritoneal exposure (Nx; n = 12); no nephrectomy, with peritoneal exposure (PD; n = 8); and nephrectomy, with peritoneal exposure (NxPD; n = 12). The nephrectomy consisted of a one-step 70% nephrectomy. The peritoneal exposure groups were infused once daily for 16 weeks with a 3.86% glucose-based dialysis solution. Development of chronic kidney disease was monitored during the experiment. Peritoneal function and morphological assessment of the peritoneal membrane were performed at the end of the experiment. ♢ During follow-up the nephrectomized groups developed uremia with remarkable renal tubular dilatation and glomerular sclerosis in the renal morphology. Functionally, uremia (Nx) and PD exposure (PD) alone showed faster small solute transport and a decreased ultrafiltration capacity, which were most pronounced in the combination group (NxPD). The presence of uremia resulted in histological alterations but the most severe fibrous depositions and highest vessel counts were present in the PD exposure groups (PD and NxPD). Significant relationships were found between the number of vessels and functional parameters of the peritoneal vascular surface area. ♢ It is possible to induce chronic kidney failure in our existing long-term peritoneal infusion model in the rat. The degree of impairment of kidney function after 16 weeks is comparable to chronic kidney disease stage IV. Uremia per se induces both functional and morphological alterations of the peritoneal membrane. An additive effect of these alterations is present with the addition of chronic kidney failure to the model. The latter makes the present long-term model important in better understanding the pathophysiology of the peritoneal membrane in PD.

Treatment of severe ultrafiltration failure with nonglucose dialysis solutions in patients with and without peritoneal sclerosis

Introduction. Ultrafiltration failure (UFF) in peritoneal dialysis (PD) patients is a reflection of changes in the peritoneal membrane, which can include mesothelial damage, neoangiogenesis, and occasionally, peritoneal fibrosis. These structural changes are probably induced by the use of bioincompatible dialysis solutions. Therefore, we investigated the effects of the treatment with a combination of nonglucose dialysis solutions in patients with severe UFF.Methods. Ten patients with UFF (net ultrafiltration <400 mL/4 h on 3.86% glucose) were treated with a combination of glycerol and icodextrin with or without amino acid-based dialysis solutions for 3 months. Four of them were diagnosed with encapsulating peritoneal sclerosis (PS), proven by peritoneal biopsies. Standard peritoneal permeability analyses (SPA), using 3.86% glucose, were performed, and dialysate CA125 appearance rate (AR-CA125) was analysed at the start, after 6 weeks and after 12 weeks. PS and non-PS patients were compared.Results. One patient underwent transplant after 6 weeks, one was withdrawn from PD because of clinical signs of encapsulating PS before the 3-month period ended. PS patients had been treated with PD for a longer duration than the non-PS patients (102 versus 52 months, P = 0.05), but no differences in baseline transport parameters or AR-CA125 were present. During the study, no differences were observed for transport characteristics when the results of the whole group at 6 and 12 weeks were compared to baseline. For the non-PS patients, however, a significant increase in the transcapillary ultrafiltration rate (from 2.2 mL/min to 2.6 mL/min, P < 0.05) and a decrease in the MTAC creatinine (from 14.3 mL/min to 12.6 mL/min, P < 0.05) were found after 6 weeks of glucose-free treatment. Free-water transport, measured as the maximum dip in the dialysate-to-plasma ratio of sodium and as the transport through the ultrasmall pores in the first minute, tended to improve, but this difference did not reach significance. In addition, the AR-CA125 increased significantly (from 2.8 U/min to 16.1 U/min, P < 0.05). Continued treatment did not reach statistical difference even after 3 months. No changes were observed in the PS patients.Conclusions. In the present study, an improvement of UFF in the non-PS patients was obtained by withdrawal of glucose-based dialysis solutions. The abnormalities in PS patients are probably irreversible. Early withdrawal of glucose-based dialysis solutions or at least a marked reduction in glucose exposure should be considered in UFF patients, but the identification of the patients who would benefit most needs further studies.

Vascular Endothelial Growth Factor in Dialysate in Relation to Intensity of Peritoneal Inflammation

Peritoneal inflammation may induce changes in peritoneal microvessels, including neoangiogenesis/vasculogenesis, leading to increased peritoneal solute transport rate (PSTR) and loss of ultrafiltration capacity. We hypothesized that an inflammatory reaction in the peritoneal cavity during peritonitis induces increased synthesis of vascular endothelial growth factor (VEGF). We therefore studied the relationship between peritoneal inflammation markers, VEGF, and transport of fluid and solutes in rats during acute peritoneal inflammation induced by lipopolysaccharide (LPS) added to standard glucose-based dialysis solution. Under ether anesthesia, male Wistar rats were injected intraperitoneally with 30 mL Dianeal 3.86% without (Control; n=6) or with LPS (microg/mL): 0.001 (LPS 0.001; n=6), 0.01 (LPS 0.01; n=7), 0.1 (LPS 0.1; n=7), 1.0 (LPS 1.0; n=8). After 8 hours, dialysate volume (IPV), peritoneal solute transport rate (PSTR) and dialysate cell count (DCC) were measured and effluent samples were collected. LPS i.p. resulted in increased PSTR and decreased IPV (p<0.005). DCC (cells/microL) and the neutrophil/macrophage ratio were higher for all LPS concentrations compared to the control group. After 8 hours, LPS-exposed rats had significantly higher dialysate levels of all investigated cytokines (TNF-alfa, MCP-1 and IL-10) than the control group. Addition of LPS resulted in increased dialysate VEGF concentrations (pg/mL) (LPS 0.001, 28.2+/-5.9; LPS 0.01, 38.9+/-11.6; LPS 0.1, 43.0+/-5.9; LPS 1.0, 46.6+/-11.3; Control, 14.5+/-9.8; p<0.0005 for all LPS vs. Control). The infusion of Dianeal 3.86% with different doses of LPS induced a strong acute intraperitoneal inflammatory reaction with increased DCC and cytokine levels, resulting in increased peritoneal solute transport and decreased IPV. LPS induced a dose-dependent parallel increase of the intraperitoneal concentrations of MCP-1, IL-10 and TNF-alfa, as well as of VEGF. These results suggest that intraperitoneal VEGF synthesis is induced in response to inflammation, and that this may be an important component in the process leading to peritoneal transport alterations.

Chronic Peritoneal Dialysis in South Asia — Challenges and Future

Chronic peritoneal dialysis (PD), especially continuous ambulatory PD (CAPD), is being increasingly utilized in South Asian countries (population of 1.4 billion). There are divergent geopolitical and socioeconomic factors that influence the growth and expansion of CAPD in this region. The majority of the countries in South Asia are lacking in government healthcare system for reimbursing renal replacement therapy. The largest utilization of chronic PD is in India, with nearly 6500 patients on this treatment by the end of 2006. A large majority of patients are doing 2 L exchanges 3 times per day, using glucose-based dialysis solution manufactured in India. Chronic PD is not being utilized in Myanmar, Bhutan, or Seychelles. Affirmative action by the manufacturing industry, medical professionals, government policy makers, and nongovernmental organizations for reducing the cost of chronic PD will enable the growth and utilization of this life-saving therapy.

Peritoneal Transport in Peritoneal Dialysis Patients Using Glucose-Based and Amino Acid-Based Solutions

To evaluate peritoneal transport of fluid and solutes in continuous ambulatory peritoneal dialysis (CAPD) patients using amino acid (AA)-based versus glucose-based dialysis solutions. Using iodine-labeled human serum albumin ((125)I-HSA) as intraperitoneal volume marker, peritoneal transport was investigated in a group of 20 clinically stable patients (11 females and 9 men, age 53 +/- 15 years) on CAPD for 15 - 101 months. Two paired 4-hour dwells, one with 1.36% glucose and one with 1.1% AA dialysis solution, were performed in each patient. Intraperitoneal dialysate volume, fluid absorption rate, and diffusive mass transport coefficients (K(BD)) and sieving coefficients (S) for glucose, creatinine, urea, potassium, and total protein were estimated for each dwell study. Dwell studies with AA solution were used to estimate K(BD) values for individual AAs. Intraperitoneal dialysate volume was higher for AA solution in comparison with glucose solution due to the higher osmolality of the AA solution. No statistically significant difference was found for K(BD) or S for creatinine, urea, potassium, or total protein in the dwell studies with either solution, whereas K(BD) for glucose was higher with AA than with glucose solution. Mean values of K(BD) of AA were similar but with high standard deviation, reflecting inter-individual variations in peritoneal transport rate. Our results indicate that the AA peritoneal transport rate is strongly dependent on transport characteristics of the individual peritoneal membrane.

Beneficial effects of icodextrin on plasma level of adipocytokines in peritoneal dialysis patients

Leptin and adiponectin, well-recognized adipocytokines, are reported to contribute to the pathogenesis of atherosclerosis. The aim of this study was to elucidate the effects of icodextrin-based dialysis solution on adipocytokine metabolism. In 12 non-diabetic anuric patients on peritoneal dialysis, dialysis solution was changed from glucose-based dialysis solution to icodextrin-based dialysis solution for 6 months. Plasma levels of leptin, adiponectin, lipids (total cholesterol, HDL-cholesterol and triglyceride), insulin, blood glucose and insulin sensitivity index by the homeostasis model assessment (HOMA-IR) were compared before and after the use of the icodextrin solution. Plasma leptin level was decreased from 15.6 (2.5-69.0) to 7.3 (2.9-45.9) ng/ml (P = 0.018) and plasma adiponectin level increased from 11.6 (6.2-19.6) to 17.6 (7.8-33.0) microg/ml (P = 0.002). A reduction in plasma insulin level from 33.1 (13.8-54.1) to 19.1 (5.8-37.3) muU/ml (P = 0.009) and HOMA-IR from 8.22 (3.68-15.09) to 5.15 (1.40-13.78) (P = 0.015) was observed. While plasma total cholesterol level remained similar, HDL-cholesterol level increased, from 36.0 (22-45) to 43.5 (30-69) mg/dl (P = 0.008) and the triglyceride level decreased, from 174.0 (140-250) to 116.5 (81-207) mg/dl (P = 0.012). Icodextrin-based dialysis solution improves abnormal adipocytokine metabolism, dyslipidaemia and insulin resistance, which are known to be associated with atherosclerosis. These results suggest that the use of icodextrin-based dialysis solution might be useful in preventing atherosclerosis in PD patients. Long-term effects of icodextrin-based dialysis solution on the atherosclerosis in peritoneal dialysis patients should be tested.

A solutions portfolio approach in peritoneal dialysis

Peritoneal membrane failure may develop during long-term peritoneal dialysis (PD). It is characterized by the occurrence of ultrafiltration failure1 and by morphologic alterations in the peritoneal tissues. These alternations consist of an increased thickness of the collagenous submesothelial compact zone of the parietal peritoneum, sometimes accompanied by loss of surface mesothelium2,3. Vascular abnormalities also have been described, including an increase in the number of vessels3,4; subendothelial hyalinosis, especially of the venules and small veins, but also of arterioles3,5, and extensive diabetiform lamellation of the capillary and mesothelial basement membranes6,7,8. Advanced glycosylation end products (AGEs) are found in peritoneal tissues, especially around the vascular wall9,10. Multiple peritonitis episodes might accelerate the development of these functional and anatomic alterations, but are clearly not the only source11. The induction of diabetiform peritoneal alterations in a peritonitis-free, long-term peritoneal exposure model in the rat12, and the relationship with the cumulative peritoneal glucose exposure in humans13,14, point to an important contribution by the current bioincompatible glucose-based dialysis solutions, and the need for new solutions that by their more favorable effects on the peritoneum and the patient as a whole can improve both PD technique and patient survival.

Vascular endothelial growth factor production and regulation in human peritoneal mesothelial cells

Vascular endothelial growth factor (VEGF) was recently found in peritoneal effluents of peritoneal dialysis (PD) patients. It was suggested that human peritoneal mesothelial cells (HMC) contribute to the intraperitoneal production of VEGF, which may augment vascular permeability, vasodilation and neoangiogenesis in the peritoneal membrane. The present study was designed to assess the influence of proinflammatory cytokines, thrombin, d-glucose and glycated albumin in the regulation of VEGF synthesis in primary HMC cultures. VEGF antigen concentrations were measured in the cell supernatant by ELISA and VEGF mRNA expression was evaluated by real time RT-PCR. Incubation of HMC with interleukin-1alpha (IL-1alpha; 10 to 100 U/mL), tumor necrosis factor-alpha (TNF-alpha; 500 to 1000 U/mL) or thrombin (1 to 10 U/mL) resulted in a time (24 to 72 hours) and concentration dependent increase in VEGF synthesis. In contrast, d-glucose (30 to 90 mmol/L), which is commonly used as an osmotic agent in peritoneal dialysis, was not able to up-regulate VEGF expression. High glucose levels even decreased VEGF production. However, exposure of HMC to Amadori-modified glycated albumin, which is generated in the peritoneal cavity in the presence of glucose-based dialysis solutions, resulted in a dose and time dependent increase in VEGF mRNA expression and antigen secretion. These results demonstrate, to our knowledge for the first time, that glycated serum albumin, not glucose, increases VEGF production in HMC. HMC play an important role as a source of intraperitoneal VEGF synthesis, and VEGF expression also is up-regulated in the presence of proinflammatory cytokines and thrombin. Additionally, these results confirm clinical data that the continuous exposure of the peritoneal membrane to glucose-based dialysis solutions is an important stimulus for VEGF expression. However, it is not glucose per se, but nonenzymatic glycation products like glycated albumin that up-regulate VEGF expression.

Replacement of Glucose with N-Acetylglucosamine in Peritoneal Dialysis Fluid—Experimental Study in Rats

Glucose is still used as an osmotic solute in peritoneal dialysis fluids, despite evidence of its local (peritoneal) and systemic toxicities. However a constant search is underway for a new, more biocompatible osmotic solute for peritoneal dialysis fluids. The present study evaluated N-acetylglucosamine (NAG) in a concentration of 220 mmol/L as an alternative to glucose for the osmotic solute in peritoneal dialysis fluid, during chronic peritoneal dialysis in rats. For 8 weeks, male Wistar rats were infused with glucose-based or NAG-based dialysis fluid. Intraperitoneal inflammation and peritoneal permeability and morphology were evaluated in all rats during the study. Repeated intraperitoneal infusion of the NAG-based dialysis fluid resulted in a weaker intra-abdominal inflammatory reaction as compared with the reaction in rats infused with glucose-based dialysis solution. At the end of the study, the concentration of hyaluronan in the peritoneal interstitium obtained from NAG-treated rats was higher than that found in the interstitium taken from animals exposed to dialysis fluid containing glucose. Also, peritoneal permeability to total protein was lower in NAG-treated rats. As an alternative to glucose, NAG used for the osmotic solute in peritoneal dialysis solution decreases the intraperitoneal inflammatory reaction induced by the process of peritoneal dialysis and, indirectly (owing to the increased hyaluronan content in the peritoneal interstitium), diminishes peritoneal permeability to protein.

Icodextrin Degradation Products in Spent Dialysate of CAPD Patients and the Rat, and its Relation with Dialysate Osmolality

Peritoneal dialysis (PD) with a 7.5% icodextrin-containing dialysis solution provides prolonged ultrafiltration compared with glucose-based dialysis solutions. Colloid osmosis is the most likely mechanism, but studies in rats suggest it is caused by an increase in osmolality due to degradation of icodextrin. Therefore, human spent dialysate was analyzed with high-performance liquid chromatography (HPLC) using gel permeation size-exclusion chromatography. An increasing peak (with a low molecular weight, < 1000 Da) was observed during the dwell. The aim of this study was to quantitate breakdown products of icodextrin (which could explain this peak) and investigate whether there was a relationship with dialysate amylase concentration and dialysate osmolality. Long-dwell effluents (dwell time 9.15- 14.30 hours) obtained from 12 PD patients using a 7.5% icodextrin solution during the night were analyzed. The following icodextrin breakdown products were measured: maltotetraose (G4), maltotriose (G3), maltose (G2), and glucose (G1). In 6 of these patients, the sugars maltoheptaose (G7), maltohexaose (G6), and maltopentaose (G5) were also determined in both effluent and plasma. In addition, G4, G3, G2, and G1 were measured in four Wistar rats during a 6-hour dwell study. In the human studies, the median distribution of the sugars in the effluent was G4,6.7%; G3,16.5%; G2, 23.1%; and G1, 53.5%. The osmolality in spent dialysate ranged between 288 and 326 mOsm/kg H2O. The median contribution of the sugars G2 - G4 was 5.4 mOsm/kg H2O. No correlation was present between dialysate osmolality and duration of the dwell (r= -0.04, p= 0.91); nor was there a relation between the concentration of G2 and duration of the dwell (r = 0.50, p = 0.10). No relationship was found between the amount of amylase and the concentration of G2 in the effluent (r = 0.49, p = 0.10), nor between the total concentration of the sugars G2 - G4 in the spent dialysate and dialysate osmolality (r = -0.31, p = 0.33). However, a strong correlation was seen between urea concentration and osmolality (r= 0.85, p < 0.001), and also between sodium concentration and dialysate osmolality in the spent dialysate (r = 0.92, p < 0.0001). The levels of the sugars G2, G3, and G4 in effluent were higher than in unused dialysate, but lower than or similar to plasma levels. Concentrations of the sugars G5, G6, and G7 were lower in spent dialysate than in unused dialysate, and higher than in plasma. In the rat study, dialysate osmolality increased with the duration of the dwell. A clear relationship was present between osmolality and concentration of the sugars G2 - G4 in the effluent. The median amount of amylase in the effluent was 1252 U/L. A 7.5% icodextrin-based dialysis solution used during the long exchange caused only a slight increase in dialysate osmolality in humans. The osmolality at the end of the dwell in the human situation was dependent mainly on concentrations of the small solutes urea and sodium in the effluent. The contribution of icodextrin degradation products was marginal. In the rat, however, a clear relationship was present between osmolality and icodextrin degradation products in spent dialysate, explaining the increased dialysate osmolality at the end of the dwell. The difference between the two species can be explained by the very high amylase concentrations in the rat, leading to a rapid degradation of icodextrin. The rat is therefore not suitable to study peritoneal fluid kinetics using icodextrin as an osmotic agent.

Hyaluronan Preserves Peritoneal Membrane Transport Properties

We have shown that intraperitoneal (i.p.) addition of hyaluronan (HA) in a single dwell study in rat could increase peritoneal fluid removal by decreasing the peritoneal fluid absorption rate. In this study, we investigated the impact of repeated use of HA on peritoneal membrane transport characteristics. Twelve male Sprague-Dawley rats received a once-daily i.p. injection of 25 mL 4.25% glucose dialysis solution without (HP group, n = 6) or with 0.025% HA (HA group, n = 6) for 1 week. Forty-eight hours after the last injection, a 4-hour dwell using 25 mL 4.25% glucose dialysis solution with i.p. volume marker and frequent dialysate and blood samplings was performed in each rat as well as in rats that did not receive any injection (control group, n = 8). Although the i.p. volumes were significantly lower in the HP and HA groups compared to the control group, i.p. volume in the HA group was significantly higher than in the HP group. Net ultrafiltration at 4 hours was 5.6 +/- 1.3 mL, 10.2 +/- 1.8 mL, and 13.2 +/- 0.6 mL for the HP, HA, and control group, respectively. The peritoneal fluid absorption rate decreased by 45% in the HA group compared to the HP group. There was no significant difference in peritoneal fluid absorption rate between the HA and the control group. No difference was found in the direct lymphatic absorption rate between the HP and HA groups [0.010 +/- 0.003 mL/minute in the HP group and 0.011 +/- 0.004 mL/min in the HA group] although they were both higher than that of the control group (0.004 +/- 0.001 mL/min). The solute transport rates were in general significantly higher in the HP group compared to the HA and control groups, and there was no significant difference between the latter two groups, except that protein transport rate was significantly lower in the HA group compared to the control group. The present study suggests that (1) repeated exposure to hypertonic glucose-based dialysis solution results in increased peritoneal solute transport rates, as well as increased peritoneal fluid absorption rates; and (2) these changes, reflecting a highly permeable peritoneal membrane, were ameliorated by repeated i.p. addition of hyaluronan. The similar changes in the direct lymphatic absorption rate in rats that received daily i.p. injection of dialysis solution suggest that direct peritoneal lymphatic absorption was not influenced by hyaluronan.